By Chong He and Amit Khanna

Dr. Stuart Kim

Dr. Stuart Kim

Is there an underlying intrinsic clock for aging that determines our lifespan? What are the regulatory factors that control our rate of aging and specify our lifespan? Dr. Kim, Professor of Developmental Biology and Genetics at Stanford University, is studying the process of aging in C. elegans (worms) and humans to answer these questions.

In C. elegans, Dr. Kim discovered that aging is partly caused by a decline in a suite of developmental transcription factors. In middle-aged worms, expression of these key developmental regulators begins to decline. This leads to a cascade of changes in expression of genes in the skin and intestine, which leads to dysfunction and physiological breakdown of these two organ systems. Rescuing the expression levels of these aging transcription factors in old worms to levels found in the young state rejuvenates the aging transcriptome and increases worm lifespan. Conversely, decreasing the expression of the aging transcription factors in young worms to levels seen in old state (by RNAi inhibition) results in a transcriptome with premature aging characteristics and decreased lifespan.

In humans, Dr. Kim found that the STAT3 and NFKB transcription factors are key drivers of aging in the kidney. Interestingly, inhibition of STAT3 activity with a drug leads to changes in gene expression in kidney cells (cultured in a dish) that resemble expression changes seen in young kidneys; that is, inhibition of STAT3 activity appears to rejuvenate the kidney’s aging transcriptome.

SAGE asked Dr. Kim some follow-up questions during the postdoc lunch:

Q: Are we any closer to finding the magic potion for extending lifespan or anti-aging therapies?

SK: I think right now we have a lot of [drug] candidates that can make you live longer. And there are a lot of molecular signaling pathways that can regulate longevity in yeast, worms and flies. So in that regard, I think we have a lot of possible approaches to extend longevity. I think anti-aging is different. Anti-aging to me is slowing down changes in a middle-aged person, or making an old person become younger. This is different than simply living longer. There are a lot of ways to live longer that don’t involve changing the aging axis. In terms of changing aging itself, I think we are not very close, because we tend to study how to live longer. There is less people study normal aging itself.

Q: Where do you place the development drift theory as compared to other theories in the field?

SK: Other than my lab, I think people don’t usually think about the development drift theory so much. But I believe in data. If you look at the difference between young and old worms in a genome-wide fashion, the development stage would be the top difference. The transcriptome shows that the most changes are in development, more than stress, DNA damage, and senescence. If you go by data and just let the data make the theory, then epigenetic changes in developmental drift come out. I don’t like to start with a theory first.

Q: What is the potential impact of your work in the field of renal transplant and treatment of renal stone formation?

SK: This is a new area that we are starting to look at. What I like about this area is that aging is the biggest factor for renal transplant success. People with kidney failure are dying because there is a shortage of donor kidneys. Kidneys get thrown away just because they are above a certain age. If you could take old kidneys and figure out which ones are actually healthier than expected for their chronologic age, we can rescue them from being thrown away. If we can figure out that an old kidney is worth the cost of transplant, we can save lots money and lives.

Q: If you can describe briefly and put in perspective where you put role of STAT3 and other sources of infection in aging subjects.

SK: STAT3 fits into the inflammation model of aging, which is that chronic inflammation is probably detrimental while acute inflammation is protective for the infection. When we look at the kidney, the major signature we get is chronic inflammation. The cause of chronic inflammation as far as I can tell is still unclear. Maybe it is caused by all the acute inflammation, or maybe there is an underline clock, which causes the baseline inflammation to rise independently from the acute inflammation. I don’t think the evidence which support adding up acute inflammation to predict chronic inflammation is very strong. I believe there is something else going on besides getting infections.

Q: Which field of basic research do you think influences your research the most?

SK: The microbiome might be one. Because you can have chronic inflammation initiated from the interaction with the microbiome from the gut. I would keep that in my mind.

Q: What is your suggestion for young scientists who are interested in pursuing aging research?

SK: I think aging is a great field because it is so unclear. It appears to me that we don’t understand the real reason of why we age. There are so many things yet to discover in front of us. I believe that there is a clock, and I am wondering if there is some sort of cell cycle clock behind this. Another suggestion is data first, theory second. I don’t it is a good idea to have a theory first: generate data to support the theory, and throw away the data that don’t support the theory.

For more information on Dr. Kim’s research check out the Kim Lab Website.